Etiology, characteristics and occurrence of heart diseases in rural Lesotho (ECHO-Lesotho): A retrospective echocardiography cohort study

Background In 2019, 600’000 people in Africa died of heart failure and heart diseases will increase on the continent. It is crucial to understand the regional etiologies and risk factors for heart failure and underlying heart diseases. However, echocardiography data from rural Africa are scarce and from Lesotho non-existent. This study aims to examine the occurrence, characteristics and etiology of heart failure and heart diseases using echocardiography data from a referral hospital in rural Lesotho. Methods We conducted a retrospective cohort study at Seboche Mission Hospital, the only referral hospital in Butha-Buthe district (Lesotho) with an echocardiography department. We included data from all individuals referred to the department between January 2020 and May 2021. From non-hospitalized patients echocardiographic diagnosis, sex and age were available, from hospitalized patients additional sociodemographic and clinical data could be extracted. Results In the study period, a total of 352 echocardiograms were conducted; 213 had abnormal findings (among them 3 children). The majority of adult participants (130/210; 64%) were female and most frequent heart diseases were hypertensive (62/210, 30%), valvular (39/210, 19%) and chronic pulmonary (37/210, 18%). Heart failure represented 11% of hospitalizations in the same period. Among the 126 hospitalized heart failure patients, the most common etiology was chronic pulmonary heart disease (32/126; 25%). Former mine workers and people with a history of tuberculosis were more likely to have a chronic pulmonary heart disease. Conclusions The leading cause of heart disease in this setting is hypertension. However, in contrast to other African epidemiological studies, chronic pulmonary heart disease is unexpectedly common. There is an urgent need to improve awareness and knowledge about lung diseases, make diagnostic and therapeutic options available and increase prevention.

Introduction During the last two decades, cardiovascular diseases have rapidly emerged as a major cause of disease and death in Africa [1]. According to the World Health Organization, cardiovascular diseases are among the top five causes of death in Africa. Almost 1.1 million people died because of cardiovascular diseases in Africa in 2019 [2]. Ischemic heart disease, stroke, and hypertensive heart diseases are identified as the three most common causes of cardiovascular death in Sub-Saharan Africa (SSA) [2].
The heart failure syndrome has been recognized as a significant contributor to cardiovascular disease burden in SSA for many decades. The increasing burden of heart failure in the region is driven by increasing urbanization, changes in lifestyle habits (decreased physical activity, increased alcohol and nicotine use), and ageing of the population, and thus, in a surge of hypertension, type 2 diabetes mellitus, dyslipidemia and obesity [3]. Mortality of patients with heart failure has been reported to be highest in Africa, compared to other low-and middle-income regions; in Africa alone the mortality of patients with heart failure was estimated at 34% [4]. The most commonly reported etiology of heart failure in low-and middle-income regions is ischemic heart disease, except for South America and Africa [5]. A recent meta-analysis from Africa including 10,098 patients from 22 studies found not ischemic/coronary heart disease but hypertensive heart disease to be the commonest cause of heart failure at 39.2%, followed by cardiomyopathies (21.4%), rheumatic heart disease (14.1%), and ischemic/coronary heart disease only at 7.2% [6]. However, data from low-and middle-income countries are scarce due to the non-availability of routine echocardiography, especially in rural areas.
The WHO estimates that cardiovascular diseases represent 14% of premature deaths due to non-communicable diseases in Lesotho [7]. Detailed data on heart diseases and heart failure in Lesotho, however, are non-existent. In this study, we describe the occurrence, characteristics, and etiology of heart diseases and heart failure, diagnosed using echocardiography, in patients from a rural referral hospital in Lesotho.

Study design
We conducted a retrospective cohort study at Seboche Mission Hospital. The secondary-level referral hospital is situated in Butha-Buthe district, Northern Lesotho, on 1800 meters above sea level. It is a public missionary hospital and serves a rural local population (Basotho), mostly subsistence farmers and migration workers. Since 2020, the hospital has an established echocardiography department that performs about 20-30 echocardiographic assessments (including electrocardiograms) per month and represents the only echocardiographic referral point for the entire district.
We included retrospective data of all individuals-children <18 years old and adultsreferred to the echocardiography department between January 2020 and May 2021 due to signs and symptoms of heart failure. From patients that were hospitalized detailed sociodemographic and clinical data was available, whereas for the others only sex and age.

Data collection
We extracted data from in-patient routine medical records, the echocardiography department patient register and the echocardiography reports. The participants' demographics, clinical information, echocardiography findings and laboratory values were entered into an electronic data capture spreadsheet by the physician and echocardiographer. Missing demographic information was collected through telephonic consultation with the patient. The data was doublechecked by an external collaborator.

Definitions
We provide detailed information about the echocardiography machine, techniques and measurements used in S1 Text. We adhered to the following clinical and echocardiographic definitions: Heart failure. Clinical syndrome of effort intolerance related to an abnormality of cardiac function, characterized by typical symptoms of shortness of breath, fatigue and leg swelling and accompanied by clinical signs of congestion, such as peripheral oedema, elevated jugular venous pressure and pulmonary crepitations [8].
Functional heart failure. Heart failure signs without cardiac abnormality, caused by another reason (e.g. severe anemia, hyperthyroidism).
Right heart failure. Tricuspid Annular Plan Systolic Excursion < 17 mm or RV systolic excursion velocity by tissue doppler imaging < 9.5 cm/s or fractional area change < 32% [9].
Hypertensive heart disease. Left ventricular (LV) hypertrophy or concentric remodeling (normal LV mass with a relative wall thickness > 0.42) with or without global systolic or diastolic left ventricular dysfunction in a patient with arterial hypertension (systolic blood pressure >140mmHg or diastolic blood pressure >90mmHg or presence of antihypertensive therapy), with neither valve disease nor segmental wall motion abnormalities [8].
Hypertrophic cardiomyopathy. A maximal end-diastolic wall thickness of �15 mm anywhere in the LV, in the absence of another cause of hypertrophy [10].
Hypertrophy of the LV in children. LV mass/height 2.7 above the 95 th percentile; severe LV hypertrophy: LV mass of at least 30% above the 95 th percentile [11]. Dilated cardiomyopathy. LV or biventricular dilation and impaired contraction, not explained by abnormal loading conditions (e.g. hypertension and valvular heart disease) or coronary artery disease [12].
Valvular heart disease. Abnormal size and/or function of the heart and a primary abnormality of a valve (i.e., presence of valve regurgitation or stenosis and thickening of cusps, leaflets, or leaflet tips, vegetations or ruptured chordae tendineae). As a subgroup of the valvular heart diseases, rheumatic heart disease was defined according to the 2012 world heart federation criteria [13].
Coronary heart disease. Typical angina pectoris and ventricular dysfunction with segmental hypo-or akinesia which could be attributed to a specific coronary artery with or without typical ECG findings [8].
Pulmonary heart disease. Right heart failure in presence of pulmonary hypertension and normal left atrium pressure, sub-divided into either chronic or acute pulmonary heart disease [8].
Pericardial heart disease. Pericardial effusion as the primary reason for the heart failure. Tuberculosis (TB) pericarditis if clinically suspected or microbiologically confirmed TB [8].
Congenital heart disease. Definition according to the American Society of Echocardiography Pediatric and Congenital Heart Disease Council [14].
Peri-/Post-partum cardiomyopathy. Cardiomyopathy with a reduced left ventricular ejection fraction (LVEF) of <45%, presenting towards the end of the pregnancy or in the months after delivery in a woman without previously known structural heart disease [15].

Statistical analysis
We used absolute and relative frequencies to describe categorical data and medians and interquartile ranges for continuous variables. Inferential statistical testing to investigate factors predicting the most common etiology of heart failure was conducted using univariate and multivariate logistic regression models. We applied two-sided p-values with alpha 0.05 level of significance and presented the results as odds ratios with 95% confidence intervals. Descriptive statistics were conducted using Microsoft Excel and inferential statistics using Stata (version 14, Stata Corporation, Austin/Texas, USA).

Ethics statement
The National Health Research and Ethics Committee of the Ministry of Health of Lesotho reviewed the study protocol and concluded that no written informed consent is needed since this is a retrospective study only involving the collection of existing data, registers and documents (ID146-2021; August 06, 2021).

Results
Between January 2020 and May 2021, a total of 352 echocardiograms were conducted at the echocardiography department of Seboche Mission Hospital. Of the 352 echocardiograms, 11 (3%) were follow-up assessments. Among the 341 included echocardiograms (335 adults and 6 children), 128 (38%) indicated normal or non-significant findings, e.g. a minimal mitral valve regurgitation without any other sign of a heart disease ( Table 1).

Heart failure: Occurrence, characteristics and etiology
Among the 210 adult individuals with abnormal findings, 118 were hospitalized due to heart failure. In the same time period, in addition, eight adult patients with functional heart failure, i.e. caused by another reason than cardiac abnormality (e.g. severe anemia), were hospitalized. Overall, at Seboche Mission hospital between January 2020 and Mai 2021, hospitalization due to heart failure represented 11% (126/1164) of all hospitalized patients. The majority of patients hospitalized due to heart failure were female (56%; 70/126) and had a median age of 66 years old (IQR 54-76). 61% (77/126) had arterial hypertension, 65% (82/126) took cardiac  Table 2). The detailed echocardiographic data of the patients hospitalized due to heart failure are listed in S1 Table. Only 48% (60/126) had a normal sized LV. Left ventricular systolic function was preserved in 60% (75/126) of participants, but severely impaired in 22% (28/126). 29% (36/126) of patients had a ventricular hypertrophy and 24% (30/126) presented with left ventricular dilatation. Moderate to severe valve regurgitation of the aortic valve accounted for 5% (6/126) of patients and of the mitral valve for 13% (16/126) of patients. 2% (2/126) of patients had a moderate to severe aortic valve stenosis and 3% (4/126) of patients a moderate to severe mitral valve stenosis. Severe tricuspid insufficiency was noted in 15% (19/126) of patients. 31% (39/126) of patients had some pericardial effusion, but in only 5% (6/126) of patients this effusion was the cause of the heart failure (S1 Table).
The most frequent etiology for heart failures were chronic pulmonary heart disease (32/126, 25%), followed by dilated cardiomyopathy (21/126, 17%) and valvular heart disease (20/126, 16%) (Fig 2). Among the valvular heart diseases, most were rheumatic origin (Table 3). Coronary heart diseases accounted for 11% (14/126) and hypertensive heart diseases represented 9% (11/126) of all reasons for hospitalization due to heart failure (Fig 2 and Table 3). 4 patients died during the hospitalization: A 70 years old male with chronic pulmonary heart disease, a 18 years old male with a fulminant acute pulmonary heart disease, a 56 years old female with dilated cardiomyopathy and a 51 years old female with a valvular (rheumatic) heart disease.

Discussion
This retrospective cohort study included all echocardiograms (n = 352) performed during a 17-month period in 2020/21 at a rural hospital in Northern Lesotho. Among the 210 adult participants with a heart disease, hypertensive heart disease (30%), valvular heart disease (19%), chronic pulmonary heart disease (18%), dilated CM (12%) and coronary heart disease (8%) were the most common etiologies. Heart failure represented a substantial burden of hospitalizations with 11% of all hospitalized patients in the same period. Among the 126 hospitalized participants with heart failure, only 48% had a normal sized LV and only 60% had a preserved left ventricular systolic function. The most common etiologies were chronic pulmonary heart disease (25%), dilated CM (17%), valvular heart disease (16%, most rheumatic), coronary heart disease (11%) and hypertensive heart disease (9%). Former mine workers and people with a history of TB were more likely to have a chronic pulmonary heart disease.
In 2019, about 600'000 people in Africa died of heart failure due to a heart disease [2]. It is estimated that the burden of heart diseases will increase in the coming decade and that the underdiagnosis rate is high [3]. In order to tackle this health problem, it is of paramount importance to understand the etiologies and risk factors for heart diseases and heart failure in the region.
In line with a recent meta-analysis of 22 African studies, hypertensive heart disease is the most common heart disease [6]. Moreover, valvular (mostly due to rheumatic origin) and cardiomyopathies are common etiologies, whereas ischemic or coronary heart diseases are-different to the rest of the world-still rather an infrequent reason at 7% of all heart failure cases, similar to our findings [6]. What is striking in our study, is the high number of chronic pulmonary heart diseases: It was the third most frequent heart disease (18%) among all assessed patients (hospitalized and non-hospitalized) and the most frequent heart disease (25%) among hospitalized patients with heart failure.
A comparable prospective echocardiography cohort study conducted at a rural referral hospital in Tanzania concluded that hypertensive heart disease (41%), followed by valvular heart disease (18%), coronary heart diseases (18%) and cardiomyopathies (15%) were the most common heart diseases [16]. Similar to the meta-analysis, they observed only 5% of pulmonary heart diseases. In contrast, a recent South African study of 119 patients with heart failure documented 12% pulmonary heart diseases, indicating, that there might be a regional difference in etiologies [17]. Chronic pulmonary heart disease or cor pulmonale is a right heart failure caused by long-term high blood pressure in the lung arteries and right ventricle, whereas the left heart works normal [18]. Most commonly it results from chronic lung diseases such as chronic obstructive pulmonary disease (COPD) [18]. The mining sector in Lesotho and South Africa is one of the main industries for Basotho, especially the men. It is well documented that Basotho mine workers have a high risk of lung diseases such as TB, COPD and silicosis [19,20]. While working conditions in the official mines have improved, illegal mining among Basotho has increased, as many South African mines have closed down or become less accessible for foreign workers [21]. Another reason for increased chronic lung diseases and thus resulting in pulmonary heart diseases, might be the exposure to indoor air pollution from biomass cooking fuels, a common practice in rural Lesotho. A meta-analysis concludes strong association of this cooking practice with COPD with highest risk in the African region [22]. HIV infection itself is a cause of pulmonary hypertension, was a risk factor in the univariate logistic regression analysis, is prevalent in the setting and thus, may have been contributing to the high proportion of this kind of heart disease [23].
Treatment options for patients with chronic pulmonary heart diseases are limited and unspecific: Improvement of the underlying cause (e.g. inhaled pulmonary vasodilator therapy and oxygen), relief of symptoms (e.g. diuretics), and prevention of complications (e.g. anticoagulation). While some of the study participants received diuretics, none were taking any medication to improve the lung function nor were anticoagulated. Awareness and knowledge about lung diseases and diagnostic equipment are scarce and anticoagulation is routinely not done due to expensive monitoring and medication.
Our study has several limitations. First, it is a retrospective cohort study based on available clinical data with the risk of sampling bias. That's the reason why we have incomplete data for non-hospitalized patients and had to focus our risk factor analysis on hospitalized patients, i.e. with acute heart failure. Nevertheless, the echocardiographic diagnosis of the heart diseases was systematically available for all study patients. Moreover, the heart failure syndrome contributes most to the mortality of heart diseases, it is important to focus on this population, as done in similar studies [6]. Second, in our setting coronary angiography, myocardial scintigraphy, stress-echocardiography and myocardial biopsies are not available. Thus, the differentiation of cardiomyopathies was not possible, and diagnosis of coronary heart disease was based on medical history, clinical examination, electrocardiogram and echocardiogram only. Third, we had no data on lung function, indoor air pollution or other cardiovascular risk factors. More research is warranted in this area.
To our knowledge, this is the first echocardiographic study from Lesotho systematically assessing the etiology of heart diseases and one of few in southern Africa. Another strength is that the study was able to determine the burden of the heart failure syndrome at a typical referral hospital in the region and evaluate the most frequent causes and its risk factors. The findings offer important insights for the region.
In conclusion, this study established the causes of heart diseases and heart failure, which is important for prevention and subsequent clinical management. The leading cause of heart disease in this setting is hypertension and it is thus crucial to improve prevention, screening and treatment of hypertension. However, in contrast to (northern) African epidemiological studies, pulmonary heart disease is unexpectedly common. Former mine workers and people with a history of TB were more likely to have a chronic pulmonary heart disease. There is an urgent need to improve awareness and knowledge about lung diseases among the community as well as clinicians, make diagnostic and therapeutic options available and increase prevention measures to reduce TB and air pollution exposure in the mines and homes of people in southern Africa.
Supporting information S1 Text. Echocardiography details. (DOCX) S1 Table. Echocardiography findings of patients hospitalized due to heart failure. (DOCX) S2 Table. Association between characteristics and most common etiology for heart failure. (DOCX)